Polyunsaturated higher fatty acids such as arachidonic acid serve in the metabolism of mammals including humans as substrates for the formation of physiologically and pathophysiologically important eicosanoids such as prostaglandins, thromboxanes, prostacyclin and leukotrienes. The pathway to prostaglandins, thromboxanes and prostacyclin is initiated by cyclooxygenase whereas the pathway to leukotrienes is initiated by 5-lipoxygenase.
Thromboxane A2, a highly unstable and biologically active compound is extremely effective in inducing smooth muscle contraction as well as platelet aggregation. The formation of this compound from prostaglandin endoperoxides takes place in various cells such as human platelets and is catalyzed by thromboxane synthase (Biochem. Biophys. Res. Commun. 80, 236 (1978)). Some 1-substituted imidazoles are known which inhibit the activity of thromboxane synthase (also often named as thromboxane synthetase) resulting in an inhibiting effect on formation of thrombosis.
Leukotrienes play an important role in inflammatory and immune reactions and may cause life threatening situations for example anaphylactic or septic shock, allergic reactions, bronchoconstriction and asthma. Because of the harmful effects of leukotrienes, numerous compounds have been investigated with regard to their inhibiting effect on 5-lipoxygenase. In Summers et al., Published European Patent Application No. EP 292,699 and Brooks et al., Published PCT Patent Applications No. WO 90/12008, for example, substituted phenyl, naphthyl and thienyl N-hydroxy urea compounds are disclosed, Which are suitable as inhibitors of 5-lipoxygenase.
To date, no compound is known which inhibits the activity of 5-lipoxygenase and thromboxane synthase simultaneously. This means that two active substances have to be administered if both enzymes (5-lipoxygenase and thromboxane synthase) have to be inhibited. There remains a need for a single active compound which can inhibit the actions of both 5-lipoxygenase and thromboxane synthase.